Preparation of cyclohexene carboxylate derivatives

ABSTRACT

The present invention provides new synthetic methods and compositions. In particular, new methods of preparing intermediates useful in the synthesis of neuraminidase inhibitors and compositions useful as intermediates that are themselves useful in the synthesis of neuraminidase inhibitors are provided.

BRIEF DESCRIPTION OF RELATED ART

[0001] U.S. patent application (having Attorney Docket No. 205.6) Ser.No. 08/702,308, filed Aug. 23, 1996, which was a continuation-in-partapplication of U.S. patent application Ser. No. 08/653,034, filed Mar.24, 1996, which was a continuation-in-part application of U.S. patentapplication Ser. No. 08/606,624, filed Feb. 26, 1996, which was acontinuation-in-part application of U.S. patent application Ser. No.08/580,567, filed Dec. 29, 1995, which was a continuation-in-partapplication of U.S. patent application Ser. No. 08/476,946, filed Jun.6, 1995, which was a continuation-in-part application of U.S. patentapplication Ser. No. 08/395,245, filed Feb. 27, 1995, all of which areincorporated herein by reference in their entirety, describe, it alia,neuraminadase inhibitors and intermediates in the synthesis ofneuraminidase inhibitor. The present invention provides processes usefulin the preparation of these compositions.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

[0002] The present invention is directed to methods of preparingcarbocyclic compounds and intermediates therefore.

OBJECTS OF THE INVENTION

[0003] Selected embodiments of the invention are directed to one or moreof the following objects:

[0004] A principal object of the invention is to provide new syntheticmethods and compositions.

[0005] An additional object of the invention is to provide new methodsof preparing intermediates useful in the synthesis of neuraminidaseinhibitors.

[0006] An additional object of the invention is to provide compositionsuseful as intermediates that are themselves useful in the synthesis ofneuraminidase inhibitors.

[0007] An additional object of the invention is to provide compositionsuseful as neuraminidase inhibitors.

SUMMARY OF THE INVENTION

[0008] One aspect of the present invention is directed to processes forthe preparation of compounds of the formula:

[0009] wherein:

[0010] R¹ is a cyclic hydroxy protecting group;

[0011] R² is a carboxylic acid protecting group;

[0012] R³ is a hydroxy protecting group; and

[0013] each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms;which process comprises reaction of a compound of the formula:

[0014] with a dehydrating reagent.

[0015] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0016] wherein:

[0017] each of R², R³ and R²⁰ are as defined above;

[0018] R⁴ is —C(R³⁰)₃;

[0019] each R⁵ is independently H or R³;

[0020] each R⁷ is independently H or an amino protecting group;

[0021] each R⁸ is independently H or R²;

[0022] each R⁹ is independently H or a thiol protecting group;

[0023] each R²¹ is independently R²⁰, Br, Cl, F, I, CN, NO₂ or N₃;

[0024] each R²² is independently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵,CR²⁰, —N(R²⁰)₂, —N(R²⁰) (R⁷), —N(R⁷)₂, —SR²⁰, —SR⁹, —S(O)R²⁰, —S(O)₂R²⁰,—S(O)OR²⁰, —S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, C(O)OR²⁰, —C(O)OR⁸,OC(O)R²⁰, —N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰),—N(R⁷)(C(O)OR²⁰), —C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂,—C(NR²⁰)(N(R²⁰)₂), —C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰))(N(R²⁰)(R⁷)),—C(N(R⁷))(N(R²⁰)(R⁷)), —C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)₂), —N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R⁷))(N(R²⁰)₂), —N(R⁷)C(N(R²⁰))(N(R²⁰)₂),—N(R⁷)C(N(R⁷))(N(R²⁰)₂), —N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)), —N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷) or W;

[0025] each R²³ is independently alkyl of 1 to 11 carbon atoms, alkenylof 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms;

[0026] each R²⁴ is independently R²³ wherein each R²³ is substitutedwith 0 to 3 R²² groups;

[0027] each R^(24a) is independently alkylene of 1 to 11 carbon atoms,alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atomsany one of which alkylene, alkenylene or alkynylene is substituted with0-3 R²² groups;

[0028] each R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenylof 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;

[0029] each R²⁹ is independently R²² or R²⁸ wherein each R²⁸ issubstituted with 0 to 3 R²² groups;

[0030] each R³⁰ is independently H, R²⁴, W or −R^(24a)W; and

[0031] each W is independently carbocycle or heterocycle wherein any oneof which carbocycle or heterocycle is substituted with 0 to 3 R²⁹groups; which process comprises reaction of a compound of the formula:

[0032] wherein R³¹ is a ketal or acetal, with a lewis acid reagent;

[0033] provided that R⁴, taken as a whole, contains:

[0034] 0 to 3 W groups substituted with 0 to 3 R²⁹ groups; and, inaddition,

[0035] 1 to 12 carbon atoms substituted with 0 to 3 R²² groups.

[0036] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0037] wherein:

[0038] R², R⁴, R⁷, R²⁰ and R²¹ are as defined above.

[0039] which process comprises reaction of a compound of the formula:

[0040] with a reducing reagent.

[0041] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0042] wherein:

[0043] R², R⁴, R⁵, R²⁰ and R²¹ are as described above; and

[0044] Y¹ is a mono-, di- or unsubstituted amino group;

[0045] which process comprises reaction of a compound of the formula:

[0046] with an amine reagent.

[0047] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0048] wherein:

[0049] R², R⁴, R²⁰, R²¹ and Y¹ are as described above; which processcomprises reaction of a compound of the formula:

[0050] with an oxidizing reagent.

[0051] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0052] wherein:

[0053] R², R⁴, R²⁰, R²¹ and Y¹ are as described above; which processcomprises reaction of a compound of the formula:

[0054] with a base.

[0055] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0056] wherein:

[0057] R², R⁴, R⁷, R²⁰, R²¹ and Y¹ are as described above;

[0058] which process comprises reaction of a compound of the formula:

[0059] with a reductive amination reagent.

DETAILED DESCRIPTION

[0060] General

[0061] The present invention is directed to methods of making thecompositions described herein. Even though the compositions of theinvention are prepared by any of the applicable techniques of organicsynthesis, the present invention provides advantageous methods foraccomplishing the preparations.

[0062] Many conventional techniques are well known in the art and willnot be elaborated here. However, many of the known techniques areelaborated in “Compendium of Organic Synthetic Methods” (John Wiley &Sons, New York), Vol. 1, Ian T. Harris6n and Shuyen Harrison, 1971; Vol.2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedusand Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G.Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J.,“Advanced Organic Chemistry, Third Edition”, (John Wiley & Sons, NewYork, 1985), “Comprehensive Organic Synthesis. Selectivity, Strategy &Efficiency in Modern Organic Chemistry. In 9 Volumes”, Barry M. Trost,Editor-in-Chief (Pergamon Press, New York, 1993 printing).

[0063] Generally, the reaction conditions such as temperature, reactiontime, solvents, workup procedures, and the like, will be those common inthe art for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions.

[0064] The terms “treated”, “treating”, “treatment”, and the like, meancontacting, mixing, reacting, allowing to react, bringing into contact,and other terms common in the art for indicating that one or morechemical entities is treated in such a manner as to convert it to one ormore other chemical entities. This means that “treating compound onewith compound two” is synonymous with “allowing compound one to reactwith compound two”, “contacting compound one with compound two”,“reacting compound one with compound two”, and other expressions commonin the art of organic synthesis for reasonably indicating that compoundone was “treated”, “reacted”, “allowed to react”, etc., with compoundtwo. “Treating” indicates the reasonable and usual manner in whichorganic chemicals are allowed to react. Normal concentrations (0.01M to10M, typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically−78° C. to 150° C., more typically −78° C. to 100° C, still moretypically 0° C. to 100° C.), solvents (aprotic or protic), reactiontimes (typically 10 seconds to 10 days, more typically 1 min. to 10hours, still more typically 10 min. to 6 hours), reaction vessels(typically glass, plastic, metal), pressures, atmospheres (typically airfor oxygen and water insensitive reactions or nitrogen or argon foroxygen or water sensitive), etc., are intended unless otherwiseindicated. The knowledge of similar reactions known in the art oforganic synthesis are used in selecting the conditions and apparatus for“treating” in a given process. In particular, one of ordinary skill inthe art of organic sysnthesis selects conditions and apparatusreasonably expected to successfully carry out the chemical reactions ofthe described processes based on the knowledge in the art.

[0065] Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

[0066] Condensation reactions are typically carried out at temperaturesnear room temperature, although for non-equilibrating, kineticallycontrolled condensations reduced temperatures (0° C. to −100° C.) arealso common. Solvents can be either protic (common in equilibratingreactions) or aprotic (common in kinetically controlled reactions).

[0067] Standard synthetic techniques such as azeotropic removal ofreaction by-products and use of anhydrous reaction conditions (e.g.inert gas environments) are common in the art and will be applied whenapplicable. Workup typically consists of quenching any unreactedreagents followed by partition between a water/organic layer system(extraction) and separating the layer containing the product. Each ofthe products of the following processes is optionally separated,isolated, and/or purified prior to its use in subsequent processes.

[0068] Embodiments

[0069] One aspect of the present invention is directed to processes forthe preparation of compounds of the formula:

[0070] R¹ is a cyclic hydroxy protecting group. A very large number ofcommon protecting groups (including cyclic hydroxy protecting groups)and corresponding chemical cleavage reactions are described in“Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley& Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; “Protecting Groups” (Georg Thieme VerlagStuttgart, New York, 1994). In particular Chapter 1, Protecting Groups:An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4,Carboxyl Protecting Groups, pages 118-154, Chapter 5, CarbonylProtecting Groups, pages 155-184, and Chapter 6, Amino ProtectingGroups, pages 185-243. Typically, the cyclic hydroxyprotecting groupsare those commonly useful as 1,2-diol protecting groups.

[0071] Typical 1,2-diol protecting groups (thus, generally where two OHgroups are taken together with the R¹ protecting functionality) aredescribed in Greene at pages 118-142 and include Cyclic Acetals andKetals (Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

[0072] More typically, 1,2-diol protecting groups include those shown inTable A, or ayalic ketals or acetals. Still more typically, cyclicketals and acetals. TABLE A

[0073] wherein R¹a is C₁-C₆ alkyl (as defined immediately below).“Alkyl” as used herein, unless stated to the contrary, is C₁-C₆hydrocarbon containing normal, secondary, tertiary or cyclic carbonatoms. Examples are methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl Ln-Bu, butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, 1-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH)₂),3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(CH(CH3)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃). Typical alkyls are methyl,ethyl, 1-propyl, and 2-propyl.

[0074] R² is a carboxylic acid protecting group. Typical carboxylic acidprotecting groups are R²⁵ (described immediately below) or thosedescribed in Greene at pages 224-276. Those described in Greene includeEsters (Methyl); Substituted Methyl Esters (9-Fluorenylmethyl,Methoxymethyl, Methylthiomethyl, Tetrahydropyranyl, Tetrahydrofuranyl,Methoxyethoxymethyl, 2-(Trimethylsilyl)ethoxymethyl, Benzyloxymethyl,Phenacyl, p-Bromophenacyl, α-Methylphenacyl, p-Methoxyphenacyl,Carboxamidomethyl, N-Phthalimidomethyl); 2-Substituted Ethyl Esters(2,2,2-Trichloroethyl, 2-Haloethyl, ω-Chloroalkyl,2-(Trimethylsilyl)ethyl, 2-Methylthioethyl, 1,3-Dithianyl-2-methyl,2-(p-Nitrophenylsulfenyl)ethyl, 2-(p-Toluenesulfonyl)ethyl,2-(2′-Pyridyl)ethyl, 2-(Diphenylphosphino)ethyl, 1-Methyl-1-phenylethyl,t-Butyl, Cyclopentyl, Cyclohexyl, Allyl, 3-Buten-1-yl,4-(Trimethylsilyl)-2-buten-1-yl, Cinnamyl, α-Methylcinnamyl, Phenyl,p-(Methylmercapto)phenyl, Benzyl); Substituted Benzyl Esters(Triphenylmethyl, Diphenylmethyl, Bis(o-nitrophenyl)methyl,9-Anthrylmethyl, 2-(9,10-Dioxo)anthrylmethyl, 5-Dibenzosuberyl,1-Pyrenylmethyl, 2-(Trifluoromethyl)-6-chromylmethyl,2,4,6-Trimethylbenzyl, p-Bromobenzyl, o-Nitrobenzyl, p-Nitrobenzyl,p-Methoxybenzyl, 2,6-Dimethoxybenzyl, 4-(Methylsulfinyl)benzyl,4-Sulfobenzyl, Piperonyl, 4-Picolyl, p-poly-Benzyl); Silyl Esters(Trimethylsilyl, Triethylsilyl, t-Butyldimethylsilyl,i-Propyldimethylsilyl, Phenyldimethylsilyl, Di-t-butylmethylsilyl);Activated Esters (Thiols); Miscellaneous Derivatives (Oxazoles,2-Alkyl-1,3-oxazolines, 4-Alkyl-5-oxo-1,3-oxazolidines,5-Alkyl-4-oxo-1,3-dioxolanes, Ortho Esters, Phenyl Group,Pentaaminocobalt(III) Complex); Stannyl Esters (Triethylstannyl,Tri-n-butylstannyl); Amides (N,N-Dimethyl, Pyrrolidinyl, Piperidinyl,5,6-Dihydrophenanthridinyl, o-Nitroanilides, N-7-Nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, p-poly-Benzenesulfonamides); andHydrazides (Hydrazides, N-Phenyl, N,N′-Diisopropyl).

[0075] R²⁵ is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbonatoms, or alkynyl of 2 to 12 carbon atoms, any one of which alkyl,alkenyl, or alkynyl is substituted with 0-3 R²² groups (R²² is describedbelow). More typically R²⁵ is alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, any one of whichalkyl, alkenyl, or alkynyl is substituted with 0-3 R²² groups. Stillmore typically, R²⁵ is alkyl of 1 to 8 carbon atoms substituted with 0-2R²² groups. Even more typically, R²⁵ is alkyl of 1, 2, 3, 4, 5, 6, 7, or8 carbon atoms. Most typically R²⁵ is methyl, ethyl, 1-propyl or2-propyl. “Alkenyl” as used herein, unless stated to the contrary, isC₁-C₆ hydrocarbon containing normal, secondary, tertiary or cycliccarbon atoms. Examples are ethenyl (—CH=CH₂), 1-prop-1-enyl (—CH=CHCH₃),1-prop-2-enyl (—CH₂CH{CH₂), 2-prop-1-enyl (—C(=CH₂)(CH₃)), 1-but-1-enyl(—CH{CHCH₂C13), 1-but-2-enyl (—CH₂CH{CHCH₃), 1-but-3-enyl(—CH₂CH₂CH{CH₂), 2-methyl-1-prop-1-enyl (—CH{C(CH₃)₂),2-methyl-1-prop-2-enyl (—CH₂C(=CH₂)(CH₃)), 2-but-1-enyl(—C(=CH₂)CH₂CH₃), 2-but-2-enyl (—C(CH₃)=CHCH₃), 2-but-3-enyl(—CH(CH₃)CH{CH₂), 1-pent-1-enyl (C=CHCH₂CH₂CH₃), 1-pent-2-enyl(—CHCH{CHCH₂CH₃), 1-pent-3-enyl (—CHCH₂CH{CHCH₃), 1-pent-4-enyl(—CHCH₂CH₂CH{CH₂), 2-pent-1-enyl (—C(=CH₂)CH₂CH₂CH₃), 2-pent-2-enyl(—C(CH₃)=CH₂CH₂CH₃), 2-pent-3-enyl (—CH(CH₃)CH{CHCH₃), 2-pent-4-enyl(—CH(CH₃)CH₂CH{CH₂) or 3-methyl-1-but-2-enyl (—CH₂CH{C(CH₃)₂). Moretypically, alkenyl groups are of 2, 3 or 4 carbon atoms.

[0076] “Alkynyl” as used herein, unless stated to the contrary, is C₁-C₆hydrocarbon containing normal, secondary, tertiary or cyclic carbonatoms. Examples are ethynyl (—C≡CH), 1-prop-1-ynyl (—C≡—CCH₃),1-prop-2-ynyl (—CH₂C—CH), 1-but-1-ynyl (—C≡CCH₂CH₃), 1-but-2-ynyl(—CH₂C≡CCH₃), 1-but-3-ynyl (—CH₂CH₂C≡CH), 2-but-3-ynyl (CH(CH₃)C≡CH),1-pent-1-ynyl (—C≡CCH₂CH₂CH₃), 1-pent-2-ynyl (—CH₂C≡CCH₂CH₃),1-pent-3-ynyl (—CH₂CH₂C≡CCH₃) or 1-pent-4-ynyl (—CH₂CH₂CH₂C≡CH). Moretypically, alkynyl groups are of 2, 3 or 4 carbon atoms.

[0077] R³ is a hydroxy protecting group. Typical R³ hydroxy protectinggroups described in Greene (pages 14-118) include Ethers (Methyl);Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl,t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,4-Methoxytetrahydrothiopyranyl, 4-MethoxytetrahydropthiopyranylS,S-Dioxido, 1-[(2—Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 35,1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2—Chloroethoxy)ethyl,1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl,1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl,2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl,p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); SubstitutedBenzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p—Cyanobenzyl,p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,Diphenylmethyl, p,p′-Dinitrobenzhydryl, 5-Dibenzosuberyl,Triphenylmethyl, α-Naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl,Tri(p-methoxyphenyl)methyl, 4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-Tris(levulinoyloxyphenyl)methyl,4,4′,4″-Tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl Ethers(Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate,Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate,4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate,Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl,9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl,Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With AssistedCleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Niotro-4-methylpentanoate,o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate,2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate,2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters(2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3tetramethylbutyl)phenoxyacetate,2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate,Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, (α-Naphthoate, Nitrate,Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate, N-Phenylcarbamate,Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); andSulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,Tosylate).

[0078] More typically, R³ hydroxy protecting groups include substitutedmethyl ethers, substituted benzyl ethers, silyl ethers, and estersincluding sulfonic acid esters, still more typically, trialkylsilylethers, tosylates, mesylates and acetates.

[0079] Each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms.Typically R²⁰ is H or alkyl of 1 to 6 carbon as described above. Stillmore typically, R²⁰ is H or methyl. More typically yet, R²⁰ is H.

[0080] This process embodiment comprises reaction of a compound of theformula:

[0081] with a dehydrating reagent. Typically the hydroxy group atposition 1 is eliminated without removing the cis-4,5-diol protectinggroup. The hydroxy group at position 1 is eliminated to form an olefinicbond between positions 1 and 6.

[0082] Typically the process comprises treating compound 4 with asuitable dehydrating agent, such as a mineral acid (HCl, H₂SO₄) orSO₂Cl₂. More typically, compound 4 is treated with SO₂Cl₂, followed byan alkanol. Still more typically, compound 4 is treated with SO₂Cl₂ in asuitable polar, aprotic solvent, such as an amine to form an olefin.More typically yet, compound 4 is treated with SO₂Cl₂ in pyridine/CH₂Cl₂at a temperature between −100° C. and 0° C., typically −100° C. and −10°C., more typically −78° C., to form compound 5.

[0083] In a typical embodiment, a solution of compound 4 and pyridine indichloromethane is cooled to −200 to −30° C. and treated portionwisewith sulfuryl chloride. After the exothermic reation subsided, theresulting slurry is quenched with ethanol, warmed to 0° C., and washedsuccessively with 16% sulfuric acid, water and 5% aqueous sodiumbicarbonate. A detailed example of this embodiment is provided asExample 4 below.

[0084] Optionally, the process of this embodiment further comprisespurifying or separating compound 5 from any other reaction products orother contaminents such as other double bond isomers, halogenated sideproducts or starting materials and reagents by treatment with a noblemetal complex. Noble metals include gold, silver, platinum, palladium,iridium, rhenium, mercury, ruthenium and osmium. Typically, the noblemetal complex of this embodiment is a complex of platinum or palladium.More typically the complex is a palladium (O) complex, still moretypically, the complex is a tetrakis(triarylphosphine)palladium (O)complex.

[0085] In a typical embodiment the organic layer of the reactioncontains a mixture of olefin and halogenated products as well asstarting material. It is concentrated in vacuo and ethyl acetate isadded. The solution is treated with pyrrolidine andtetrakis(triphenylphosphine)palladium(O) at ambient temperature,followed by washing with 16% sulfuric acid. The organic layer isfiltered through a pad of silica gel and eluted with ethyl acetate. Thefiltrate is concentrated in vacuo. The residue is dissolved in ethylacetate at reflux and hexane is added. Upon cooling, the productcrystallizes and is separated by filtration and washed with 14% ethylacetate in hexane. After drying in vacuo, 5 was obtained. A detailedexample of this embodiment is provided as Example 4 below.

[0086] In another example of this embodiment compound 5 is of theformula:

[0087] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0088] wherein:

[0089] R², R³ and R²⁰ are as defined above.

[0090] R⁴ is described below.

[0091] W is carbocycle or heterocycle wherein any one of whichcarbocycle or heterocycle is substituted with 0 to 3 R²⁹ groups (R²⁹ isdescribed below).

[0092] W is a carbocycle or heterocycle, with the proviso that each W isindependently substituted with 0 to 3 R²⁹ groups (R²⁹ is describedbelow). W carbocycles and heterocycles are stable chemical structures.Such structures are isolatable in measurable yield, with measurablepurity, from reaction mixtures at temperatures from −78° C to 200° C.Each W is independently substituted with 0 to 3 R²⁹ groups. Typically, Wis a saturated, unsaturated or aromatic ring comprising a mono- orbicyclic carbocycle or heterocycle. More typically, W has 3 to 10 ringatoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6ring atoms. The W rings are saturated when containing 3 ring atoms,saturated or monounsaturated when containing 4 ring atoms, saturated, ormono- or diunsaturated when containing 5 ring atoms, and saturated,mono- or diunsaturated, or aromatic when containing 6 ring atoms.

[0093] When W is carbocyclic, it is typically a 3 to 7 carbon monocycleor a 7 to 12 carbon atom bicycle. More typically, W monocycliccarbocycles-have 3 to 6 ring atoms, still more typically 5 or 6 ringatoms. W bicyclic carbocycles typically have 7 to 12 ring atoms arrangedas a bicyclo [4,5], [5,5], [5,6] or [6,6] system, still more typically,9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

[0094] A W heterocycle is typically a monocycle having 3 to 7 ringmembers (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, 0,P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atomsand 1 to 3 heteroatoms selected from N, O, P, and S). More typically, Wheterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and1 to 2 heteroatoms selected from N, O, and S), still more typically, 5or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selectedfrom N and S). W heterocyclic bicycles typically have 7 to 10 ring atoms(6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S)arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still moretypically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]system. “Heterocycle” as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A.; “Principlesof Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and “J. Am. Chem. Soc.”, 82:5566 (1960).

[0095] Examples of heterocycles include by way of example and notlimitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,O-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

[0096] By way of example and not limitation, carbon bonded heterocyclesare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0097] By way of example and not limitation, nitrogen bondedheterocycles are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or carboline. Still moretypically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0098] Typically W heterocycles are selected from pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, orpyrrolyl.

[0099] More typically, the heterocycle of W is bonded through a carbonatom or nitrogen atom thereof. Still more typically W heterocycles arebonded by a stable covalent bond through a carbon or nitrogen atomthereof. Stable covalent bonds are chemically stable structures asdescribed above.

[0100] W optionally is selected from the group consisting of:

[0101] R⁵ is H or R³.

[0102] R⁷ is H or an amino protecting group. R⁷ amino protecting groupsare described by Greene at pages 315-385. They include Carbamates(methyl and ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluoroenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,4-methoxyphenacyl); Substituted Ethyl (2,2,2-trichoroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Groups WithAssisted Cleavage (2-methylthioethyl, 2-methylsulfonylethyl,2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl,4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl,2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl); GroupsCapable of Photolytic Cleavage (m-nitrophenyl, 3,5-dimethoxybenzyl,o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,phenyl(o-nitrophenyl)methyl); Ureα-Type Derivatives(phenothiazinyl-(10)-carbonyl, N′-p-toluenesulfonylaminocarbonyl,N′-phenylaminothiocarbonyl); Miscellaneous Carbamates (t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl,Isonicotinyl, p-(p′-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl,N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl,N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide,N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides WithAssisted Cleavage (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,N-acetoacetyl, (N′-dithiobenzyloxycarbonylamino)acetyl,N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine,N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl,4,5-diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-phthalimide,N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3-5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl, N-allyl,N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary AmmoniumSalts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl,N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene,N-ferrocenylmethyl, N-2-picolylamine N′-oxide), Imine Derivatives(N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene,N,(N′,N′-dimethylaminomethylene, N,N′-isopropylidene,N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene); EnamineDerivatives (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives(N-borane derivatives, N-diphenylborinic acid derivatives,N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N-copper orN-zinc chelate); N-N Derivatives (N-nitro, N-nitroso, N-oxide); N-PDerivatives (N-diphenylphosphinyl, N-dimethylthiophosphinyl,N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl,N-diphenyl phosphoryl); N-Si Derivatives; N-S Derivatives; N-SulfenylDerivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives(N-p-toluenesulfonyl, N-benzenesulfonyl,N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-trimethoxybenzenesulfonyl,N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl,N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,N-2,6-dimethoxy-4-methylbenzenesulfonyl,N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,N-4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl,N-trifluoromethylsulfonyl, N-phenacylsulfonyl). Typically, R⁷ is H or a—C(O)R²⁵ (R²⁵ is described above).

[0103] R⁸ is H or R². Typically R⁸ is H.

[0104] R⁹ is H or a thiol protecting group. R⁹ amino protecting groupsare described by Greene at pages 277-308. They include Thioethers(S-Benzyl, S-p-Methoxybenzyl, S-o- or p-Hydroxy- or Acetoxybenzyl,S-p-Nitrobenzyl, S-4-Picolyl, S-2-Picolyl N-Oxide, S-9-Anthrylmethyl,S-9-Fluorenylmethyl, S-Ferrocenylmethyl); S-Diphenylmethyl, SubstitutedS-Diphenylmethyl, and S-Triphenylmethyl Thioethers (S-Diphenylmethyl,S-Bis(4-methoxyphenyl)methyl, S-5-Dibenzosuberyl, S-Triphenylmethyl,S-Diphenyl-4-pyridylmethyl, S-Phenyl, S-2,4-Dinitrophenyl, S-t-Butyl,S-1-Adamantyl); Substituted S-Methyl Derivatives Monothio, Dithio, andAminothio Acetals (S-Methoxymethyl, S-Isobutoxymethyl,S-2-Tetrahydropyranyl, S-Benzylthiomethyl, S-Phenylthiomethyl,Thiazolidines, S-Acetamidomethyl, S-Trimethylacetamidomethyl,S-Benzamidomethyl, S-Acetyl-, S-Carboxy-, and S-Cyanomethyl);Substituted S-Ethyl Derivatives (S-2-Nitro-1-phenylethyl,S-2-(4′-Pyridyl)ethyl, S-2-Cyanoethyl, S-2,2-Bis(carboethoxy)ethyl,S-1-m-Nitrophenyl-2-benzoylethyl, S-2-Phenylsulfonylethyl,S-1-(4-Methylphenylsulfonyl)-2-methylprop-2-yl); Silyl Thioethers,Thioesters, (S-Acetyl Derivative, S-Benzoyl Derivative,S-N-[[(p-Biphenylyl)isopropoxy]carbonyl]-N-methyl-7-aminobutyrate,S-N-(t-Butoxycarbonyl)-N-methyl-γ-aminobutyrate); ThiocarbonateDerivatives (S-2,2,2-Trichloroethoxycarbonyl, S-t-Butoxycarbonyl,S-Benzyloxycarbonyl, S-p-Methoxybenzyloxycarbonyl); ThiocarbamateDerivatives (S-(N-Ethyl), S-(N-Methoxymethyl); MiscellaneousDerivatives, Unsymmetrical Disulfides (S-Ethyl, S-t-Butyl, SubstitutedS-Phenyl); Sulfenyl Derivatives (S-Sulfonate, S-Sulfenylthiocarbonate,S-3-Nitro-2-pyridinesulfenyl Sulfide); Protection for Dithiols, DithioAcetals and Ketals (S,S′-Methylene, S,S′-Isopropylidene, andS,S′-Benzylidene, S,S′-p-Methoxybenzylidene); Protection for Sulfides(S-Methylsulfonium Salt, S-Benzyl- and S-4-Methoxybenzylsulfonium Salt,S-1-(4-Phthalimidobutyl)sulfonium Salt); S-P Derivatives(S-(Dimethylphosphino)thioyl, S-(Diphenylphosphino)thioyl);

[0105] Each R²¹ is independently R²⁰, Br, Cl, F, I CN, NO₂ or N₃.Typically, R²¹ is Cl, F or R²⁰, more typically, R²⁰, still moretypically, H.

[0106] Each R²² is independently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵,—OR²⁰, —N(R²⁰)₂, —N(R²⁰)(R⁷), —N(R⁷)₂, —SR²⁰, —SR⁹, —S(O)R²⁰, —S(O)₂R²⁰,—S(O)OR²⁰, —S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, C(O)OR²⁰, —C(O)OR⁸,OC(O)R²O, —N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰),—N(R⁷)(C(O)OR²⁰), —C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂,—C(NR²⁰)(N(R²⁰)₂), —C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰))(N(R²⁰)(R⁷)),—C(N(R⁷))(N(R²⁰)(R⁷)), —C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)₂), —N(R²⁰)C(N(R²⁰)) (N(R²⁰) (R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂), —N(R⁷)C (N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷)) (N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷) or W.

[0107] Typically R²² is F, Cl, Br, I, CN, N₃, —NO₂, —OR⁵, —OR²⁰,—N(R²⁰)₂, —N(R²⁰)(R⁷), —N(R⁷)₂, —SR²⁰, —SR⁹, —S(O)R²⁰, —S(O)₂R²⁰,—S(O)OR²⁰, —S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, C(O)OR²⁰, —C(O)OR⁸, =O, =S,=N(R²⁰) or =N(R⁷). More typically R²² is F, Cl, Br, —CN, N₃, —NO2, —OR⁵,—OR²⁰, —N(R²⁰)₂, —N(R²⁰)(R⁷), —N(R⁷)₂, —C(O)OR²⁰, —C(O)OR⁸,or =O. Stillmore typically R²² is F, Cl, Br, —CN, N₃, —NO₂, —OR²⁰, —N(R²⁰)₂,—C(O)OR²⁰ or =O. More typically yet R²² is F, Cl, Br, —CN, —OH, —N(H)₂,—C(O)OR²⁰ or =O.

[0108] Each R²³ is independently alkyl of 1 to 11 carbon atoms, alkenylof 2 to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms. Moretypically R²³ is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbonatoms, or alkynyl of 2 to 8 carbon atoms, still more typically, R²³ isalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynylof 2 to 6 carbon atoms. More typically yet, R²³ is R²⁵.

[0109] Each R²⁴ is independently R²³ wherein each R²³ is substitutedwith 0 to 3 R²² groups. Each of the typical embodiments of R²³ and R²²are typical of R²⁴. More typically R²⁴ is substituted with 0, 1, 2, or 3R²² groups.

[0110] R^(24a) is independently alkylene of 1 to 11 carbon atoms,alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atomsany one of which alkylene, alkenylene or alkynylene is substituted with0-3 R²² groups. More typically R^(24a) is alkylene of 1 to 8 carbonatoms, alkenylene of 2 to 8 carbon atoms, or alkynylene of 2 to 8 carbonatoms, still more typically, R^(24a) is alkylene of 1 to 6 carbon atoms,alkenylene of 2 to 6 carbon atoms, or alkynylene of 2 to 6 carbon atoms.More typically yet, R^(24a) is CH₂—, CH₂CH₂—, CH₂CH₂CH₂— or —C(H)(CH₃)—.

[0111] Each R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenylof 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms. Moretypically R²⁸ is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbonatoms, or alkynyl of 2 to 8 carbon atoms, still more typically, R²⁸ isalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynylof 2 to 6 carbon atoms. More typically yet, R²⁸ is R²⁵.

[0112] Each R²⁹ is independently R²² or R²⁸ wherein each R²⁸ issubstituted with 0 to 3 R²² groups. Each of the typical embodiments ofR²⁸ and R²² are typical of R²⁹. More typically R²⁹ is substituted with0, 1, 2, or 3 R²² groups.

[0113] Each R³⁰ is independently H, R²⁴, W or —R^(24a)W.

[0114] R⁴ is —C(R³⁰)₃, provided that R⁴, taken as a whole, contains 0 to1 W groups (W is described above) substituted with 0 to 3 R²⁹ groups(R²⁹ is described above); and, in addition, 1 to 12 carbon atomssubstituted with 0 to 3 R²² groups (R²² is described above). Exemplaryembodiments of R⁴ are provided as U₁ embodiments in the documents citedin the “Brief Description of Related Art” above.

[0115] Typically one R³⁰ is H. More typically, one R³⁰ is H and theremaining two R³⁰'s are independently R²⁴, W or —R^(24a)W. Moretypically yet, one R³⁰ is H, one R³⁰ is R²⁴ and the remaining R³⁰ isindependently R²⁴, W or —R^(24a)W.

[0116] In one embodiment of R⁴, one R³⁰ is H, one R³⁰ is R²⁵ and one R³⁰is R²⁴, W or —R^(24a)W. Typically, one R³⁰ is H and two R³⁰'s are R²⁵.In another embodiment of R⁴, one R³⁰ is H, one R³⁰ is —R24aW and one R³⁰is R²⁴, W or —R^(24a)W. Typically, one R³⁰ is H, one R³⁰ is —R^(24a)Wand one R³⁰ is R²⁴. In another embodiment, one R³⁰ is H and two R³⁰'sare alkyl of 1 to 6 carbon atoms.

[0117] In another embodiment, R⁴ is:

[0118] wherein R²⁶ is H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, OCH₃, —OAc (—O—C(O)CH₃), —H, —NH₂, or —SH, typically H, —CH₃ or —CH₂CH₃.

[0119] Typically each R⁴ (taken as a whole) contains 0-3 W groups eachof which is independently substituted with 0-3 R²⁹ groups; and each R⁴(taken as a whole) in addition contains 1-12 carbon atoms, each carbonatom of which is independently substituted with 0-3 R²² groups. Moretypically each R⁴ contains 0, 1 or 2 such W groups, more typically yet,0 or 1 such W group.

[0120] In another embodiment, each R³⁰ group (taken as whole) of R⁴ isnot so electron withdrawing as to prevent the formation of compound 11.Lowry, T. H. and Richardson, K. S. “Mechanism and Theory in OrganicChemistry” (Harper & Row, 1976) at section 2.2, pages 60-71, and March,J. “Advanced Organic Chemistry” (McGraw-Hill, 1977) at Chapter 9,Quantitative Treatments of the Effect of Structure on Reactivity”, pages251-259, provide details of the electron withdrawing properties ofsubstitutent groups. In another embodiment, each R³⁰ group (taken aswhole) of R⁴ has a Hammett (σ_(para) value of less than about 1,typically less than about 0.75, more typically less than about 0.5. Inanother embodiment, each R³⁰ group (taken as whole) of R⁴ has a Hammettσ_(para) value of −1.0 to 1.0, more typically −0.75 to 0.75, moretypically yet −0.5 to 0.5.

[0121] This process embodiment comprises reaction of a compound of theformula:

[0122] wherein R³¹ is a ketal or acetal, with a lewis acid reagent.Typically R³¹ is —C(R³⁰)₂— wherein R³⁰ is as described above.

[0123] Typically, compound 10 is reacted with a Lewis acid catalystcommon in the art, such as BF₃.Et₂O, TiCl₃, TMSOTf, SmI₂(THF)₂, LiClO₄,Mg(ClO₄)₂, Ln(OTf)₃ (where Ln=Yb, Gd, Nd), Ti(Oi—Pr)₄, AlCl₃, AlBr₃,BeCl₂, CdCl₂, ZnCl₂, BF₃, BCl₃, BBr₃, GaCl₃, GaBr₃, TiCl₄, TiBr₄, ZrCl₄,SnCl₄, SnBr₄, SbCl₅, SbCl₃, BiCl₃, FeCl₃, UCl₄, ScCl₃, YCl₃, LaCl₃,CeCl₃, PrCl₃, NdCl₃, SmCl₃, EuCl₃, GdCl₃, TbCl₃, LuCl₃, DYCl₃, HoCl₃,ErCl₃, TmCl₃, YbCl₃, Znl₂, Al(OPr^(i))₃, Al(acac)₃, ZnBr₂, or SnCl₄.Optionally, compound 10 is also treated with a reducing reagent. Typicalreducing reagents are of the form B(R³⁰)₃ such as BH₃. Optionallyreducing reagents of the form B(R³⁰)₃ are complexed with common solventssuch as diethylether and dimethylsulfide. A wide range of boranereducing reagents are known and will not be described in detail here.For example Brown, H. C. “Boranes in Organic Chemistry”, (Cornell Univ.Press, Ithaca, N.Y., 1972) (Brown) provides a very large number ofexamples such as is found in Part Four, Selective Reductions, pages209-251, Part Five, Hydroboration, pages 255-297, and Part Six,Organoboranes, pages 301-446.

[0124] In a typical embodiment, compound 10 is treated with a lewis acidin a nonprotic solvent. More typically, compound 10 is treated with alewis acid and a reducing reagent in a nonprotic solvent.

[0125] In a typical embodiment, a solution of 10 in dichlorormethane iscooled and treated with borane-methyl sulfide complex and trimethylsilyltrifluoromethanesulfonate. 10% Aqueous sodium bicarbonate solution isslowly added. The mixture is warmed to ambient temperature and stirred.The organic layer is filtered and concentrated in vacuo to leavecompound 11. A detailed example of this embodiment is provided asExample 6 below.

[0126] In another example process of this embodiment compound 11 is ofthe formula:

[0127] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0128] wherein:

[0129] R², R⁴, R⁷, R²⁰ and R²¹ are as defined above.

[0130] This process embodiment comprises reaction of a compound of theformula:

[0131] with a reducing reagent.

[0132] The azide of compound 30 is reduced to form compound 31.

[0133] Typically the process comprises treating compound 30 with areducing agent to form compound 31. More typically the process comprisestreating compound 30 with hydrogen gas and a catalyst (such as platinumon carbon or Lindlar's catalyst), or reducing reagents (typically atrisubstituted phosphine such as trialkyl (P(R²⁵)₃) or triaryl phosphine(PW₃, e.g. triphenylphosphine). More typically still, the processcomprises 20 treating compound 30 with triphenylphosphine and a base toform compound 31.

[0134] Typically, compound 30 is disolved in a suitable polar, aproticsolvent such as anhydrous acetonitrile. A solution of anhydroustriphenylphosphine in a suitable solvent such as anhydroustetrahydrofuran or a mixture of solvents is added dropwise. The mixtureis heated at reflux then concentrated in vacuo to leave compound 5. Adetailed example of this embodiment is provided as Example 9 below.

[0135] In another embodiment of this process compound 31 is of theformula:

[0136] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0137] wherein:

[0138] R², R⁴, R⁵, R²⁰ and R²¹ are as described above.

[0139] Y¹ is a mono-, di- or unsubstituted amino group. Typically Y¹ isof the formula —N(R³⁰)₂, a phthalimide or is a nitrogen containingheterocycle (defined above under W), more typically, Y¹ is aphthalimide, more typically yet, a phthalimide salt.

[0140] This process embodiment comprises reaction of a compound of theformula:

[0141] with an amine reagent. Typically, the amine reagent is of theformula HY¹ or a salt of HY¹, such as, by way of example, NH₃ (McManns,et al., “Bull Soc. Chim. France” 850 (1947)), HY¹ generally (Moussevon,M., et al., “Synth. Commun.” 3:177 (1973)) or phthalimide (Gabriel, etal., “Ber.” 20:2224 (1887) or Gibson, et al., “Angew. Chem. Int.”,7:919-930 (1968)).

[0142] The process comprises treating compound 40 with the amine reagentto produce compound 32. More typically, compound 40 is treated with theamine reagent in a suitable polar a protic solvent (e.g. CH₃CN, DMF orTHF). Optionally compound 40 is treated with the amine reagent and abase. Typical details of this process embodiment can be found in March,“Advanced Organic Chemistry” 4th. ed., pp 425-427.

[0143] In another embodiment of this process compound 41 is of theformula:

[0144] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0145] wherein:

[0146] R², R⁴, R²⁰, R²¹ and Y¹ are as described above;

[0147] This process embodiment comprises reaction of a compound of theformula:

[0148] with an oxidizing reagent. A wide range of suitable oxidationreagents are common in the art and will not be detailed here. Forexample House, H. O. “Modern Synthetic Reactions, Second Edition”,Chapter 5, pages 259-273, describes the selective oxidation of alcohols.Typical reagents include CrO₃, Na₂Cr₂O₇, KMnO₄, PDC and PCC. Typicaldetails of this process embodiment can be found in Larock,“Comprehensive Organic Transformations”, pp. 604-614; Corey et al.,“Tetrahedron Lett.” 31:2647-50 (1975); Ley et al., “Chem. Common” 1625(1987); Sweon, et al., “J. Org. Chem.” 43:2480-2 (1978); and Martin, etal., “J. Org. Chem.” 48:4155-56 (1983). Solvents typically include inertpolar solvents (e.g. CH₂Cl₂, toluene or CH₃CN).

[0149] In another embodiment of this process compound 51 is of theformula:

[0150] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0151] wherein:

[0152] R², R⁴, R²⁰, R²¹ and Y¹ are as described above;

[0153] This process embodiment comprises reaction of a compound of theformula:

[0154] with a base. Typically the base is a hindered amine or hinderedalkoxide or the salts of either. More typically the base is of theformula NaOR²⁵, KOR²⁵ or NR²⁵ ₃, more typically yet, DBN, DBU ordiisopropyl ethyl amine.

[0155] In another embodiment of this process compound 61 is of theformula:

[0156] Another aspect of the present invention is directed to processesfor the preparation of compounds of the formula:

[0157] wherein:

[0158] R², R⁴, R⁷, R²⁰ ₁ R²¹ and Y¹ are as described above;

[0159] This process embodiment comprises reaction of a compound of theformula:

[0160] with a reductive amination reagent. Typical details of andreferences to this process embodiment can be found in Larock, op. cit.,pp. 421-425. Another typical description (NaCNBH₃ method) is Borch, “J.Am. Chem. Soc.” 93:2897-2904 (1971).

[0161] Schemes 1 and 2 depict embodiments of the invention. Detaileddescriptions of the processes of Schemes 1 and 2 are provided in theExamples (below).

[0162] Additional individual process embodiments of the inventioninclude any one or sequential combination of processes AA, AB, AC, AD,AE, AF, AG, AH, AI, AJ, or AK of Schemes 1 and 2. “Sequentialcombination” as used herein means more than one process wherein theindividual processes are performed one after the other in the ordershown. Isolation, separation, purification is optionally performed priorto any of the individual processes.

[0163] Additional individual process embodiments of the inventioninclude any one or sequential combination of the processes of Example 1,Example 2, Example 3, Example 4, Example 5, Example 6, Example 7,Example 8, Example 9, Example 10, Example 11, Example 12 or Example 13.

[0164] Scheme 3 depicts the synthesis of the neuraminidase inhibitor 206(R=H₂) by use of alternative nitrogen nucleophiles (March, “AdvancedOrganic Chemistry” 4th. ed., pp 425-427) to open the epoxide 201.Oxidation of azidoalcohol 202 gives ketone 203 (Larock, “ComprehensiveOrganic Transformations”, pp. 604-614) in which the P-axial NR groupisomerizes to the α-equatorial configuration 204. Reductive amination ofthe ketone 204 (Larock, op. cit., pp. 421-425) gives the P-equatorialamine 205 which is acetylated to afford 206. Cleavage of the R moiety(Greene, “Protective Groups in Organic Synthesis”, pp. 218-287) givesthe neuramidase inhibitor 206 (R=H₂).

[0165] Additional individual process embodiments of the inventioninclude any one or sequential combination of processes AL, AM, AN, AO,or AP of Scheme 3.

[0166] Modifications of each of the above schemes leads to variousanalogs of the specific exemplary materials produced above. The abovecited citations describing suitable methods of organic synthesis areapplicable to such modifications.

[0167] In each of the above exemplary schemes it may be advantageous toseparate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified (hereinafter separated) to the desired degreeof homogeneity by the techniques common in the art. Typically suchseparations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example, size exclusion or ion exchange chromatography,high, medium, or low pressure liquid chromatography, small scale andpreparative thin or thick layer chromatography, as well as techniques ofsmall scale thin layer and flash chromatography.

[0168] Another class of separation methods involves treatment of amixture with a reagent selected to bind to or render otherwise separablea desired product, unreacted starting material, reaction by product, orthe like. Such reagents include adsorbents or absorbents such asactivated carbon, molecular sieves, ion exchange media, or the like.Alternatively, the reagents can be acids in the case of a basicmaterial, bases in the case of an acidic material, binding reagents suchas antibodies, binding proteins, selective chelators such as crownethers, liquid/liquid ion extraction reagents (LIX), or the like.

[0169] Selection of appropriate methods of separation depends on thenature of the materials involved. For example, boiling point, andmolecular weight in distillation and sublimation, presence or absence ofpolar functional groups in chromatography, stability of materials inacidic and basic media in multiphase extraction, and the like. Oneskilled in the art will apply techniques most likely to achieve thedesired separation.

[0170] Stereoisomers

[0171] The compounds of the invention are enriched or resolved opticalisomers at any or all asymmetric atoms. For example, the chiral centersapparent from the depictions are provided as the chiral isomers orracemic mixtures. Both racemic and diasteromeric mixtures, as well asthe individual optical isomers isolated or synthesized, substantiallyfree of their enantiomeric or diastereomeric partners, are all withinthe scope of the invention.

[0172] One or more of the following enumerated methods are used toprepare the enantiomerically enriched or pure isomers herein. Themethods are listed in approximately their order of preference, i.e., oneordinarily should employ stereospecific synthesis from chiral precursorsbefore chromatographic resolution before spontaneous crystallization.

[0173] Stereospecific synthesis is described in the examples. Methods ofthis type conveniently are used when the appropriate chiral startingmaterial is available and reaction steps are chosen do not result inundesired racemization at chiral sites. One advantage of stereospecificsynthesis is that it does not produce undesired enantiomers that must beremoved from the final product, thereby lowering overall syntheticyield. In general, those skilled in the art would understand whatstarting materials and reaction conditions should be used to obtain thedesired enantiomerically enriched or pure isomers by stereospecificsynthesis. If an unexpected racemization occurs in a method thought tobe stereospecific then one needs only to use one of the followingseparation methods to obtain the desired product.

[0174] If a suitable stereospecific synthesis cannot be empiricallydesigned or determined with routine experimentation then those skilledin the art would turn to other methods. One method of general utility ischromotographic resolution of enantiomers on chiral chromatographyresins. These resins are packed in columns, commonly called Pirklecolumns, and are commercially available. The columns contain a chiralstationary phase. The racemate is placed in solution and loaded onto thecolumn, and thereafter separated by HPLC. See for example, ProceedingsChromatographic Society—International Symposium on Chiral Separations,Sept. 3-4, 1987. Examples of chiral columns that could be used to screenfor the optimal separation technique would include Diacel Chriacel OD,Regis Pirkle Covalent Dphenylglycine, Regis Pirkle Type 1A, AstecCyclobond II, Astec Cyclobond III, Serva Chiral D-DL=Daltosil 100,Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column,Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Notall of these columns are likely to be effective with every racemicmixture. However, those skilled in the art understand that a certainamount of routine screening may be required to identify the mosteffective stationary phase. When using such columns it is desireable toemploy embodiments of the compounds of this invention in which thecharges are not neutralized, e.g., where acidic functionalities such ascarboxyl are not esterified or amidated.

[0175] Another method entails converting the enantiomers in the mixtureto diasteriomers with chiral auxiliaries and then separting theconjugates by ordinary column chromatography. This is a very suitablemethod, particularly when the embodiment contains free carboxyl, aminoor hydroxyl that will form a salt or covalent bond to a chiralauxiliary. Chirally pure amino acids, organic acids or organosulfonicacids are all worthwhile exploring as chiral auxiliaries, all of whichare well known in the art. Salts with such auxiliaries can be formed, orthey can be covalently (but reversibly) bonded to the functional group.For example, pure D or L amino acids can be used to amidate the carboxylgroup of embodiments of this invention and then separated bychromatography.

[0176] Enzymatic resolution is another method of potential value. Insuch methods one prepares covalent derivatives of the enantiomers in theracemic mixture, generally lower alkyl esters (for example of carboxyl),and then exposes the derivative to enzymatic cleavage, generallyhydrolysis. For this method to be successful an enzyme must be chosenthat is capable of stereospecific cleavage, so it is frequentlynecessary to routinely screen several enzymes. If esters are to becleaved, then one selects a group of esterases, phosphatases, andlipases and determines their activity on the derivative. Typicalesterases are from liver, pancreas or other animal organs, and includeporcine liver esterase.

[0177] If the enatiomeric mixture separates from solution or a melt as aconglomerate, i.e., a mixture of enantiomerically-pure crystals, thenthe crystals can be mechanically separated, thereby producing theenantiomerically enriched preparation. This method, however, is notpractical for large scale preparations and is of no value for trueracemic compounds.

[0178] Asymmetric synthesis is another technique for achievingenantiomeric enrichment. For example, a chiral protecting group isreacted with the group to be protected and the reaction mixture allowedto equilibrate. If the reaction is enantiomerically specific then theproduct will be enriched in that enantiomer.

[0179] Further guidance in the separation of enantiomeric mixtures canbe found, by way of example and not limitation, in “Enantiomers,Racemates, and resolutions”, Jean Jacques, Andre Collet, and Samuel H.Wilen (Krieger Publishing Company, Malabar, Fla., 1991, ISBN0-89464-618-4). In particular, Part 2, “Resolution of EnantiomerMixture”, pages 217-435; more particularly, section ₄, “Resolution byDirect Crystallization”, pages 217-251, section 5, “Formation andSeparation of Diastereomers”, pages 251-369, section 6,“Crystallization-Induced Asymmetric Transformations”, pages 369-378, andsection 7, “Experimental Aspects and Art of Resolutions”, pages 378-435;still more particularly, section 5.1.4, “Resolution of Alcohols,Transformation of Alcohols into Salt-Forming Derivatives”, pages263-266, section 5.2.3, “Covalent Derivatives of Alcohols, Thiols, andPhenols”, pages 332-335, section 5.1.1, “Resolution of Acids”, pages257-259, section 5.1.2, “Resolution of Bases”, pages 259-260, section5.1.3, “Resolution of Amino Acids”, page 261-263, section 5.2.1,“Covalent Derivatives of Acids”, page 329, section 5.2.2, “CovalentDerivatives of Amines”, pages 330-331, section 5.2.4, “CovalentDerivatives of Aldehydes, Ketones, and Sulfoxides”, pages 335-339, andsection 5.2.7, “Chromatographic Behavior of Covalent Diastereomers”,pages 348-354, are cited as examples of the skill of the art.

Salts and Hydrates

[0180] The compositions of this invention optionally comprise salts ofthe compounds herein, for example, Na⁺, Li⁺, K⁺, Ca⁺⁺ and Mg⁺⁺. Suchsalts may include those derived by combination of appropriate cationssuch as alkali and alkaline earth metal ions or ammonium and quaternaryamino ions with an acid anion moiety. Monovalent salts are preferred ifa water soluble salt is desired.

[0181] Metal salts typically are prepared by reacting the metalhydroxide with a compound of this invention. Examples of metal saltswhich are prepared in this way are salts containing Li⁺, Na⁺, and K⁺. Aless soluble metal salt can be precipitated from the solution of a moresoluble salt by addition of the suitable metal compound.

[0182] In addition, salts may be formed from acid addition of certainorganic and inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organicsulfonic acids, to basic centers, typically amines. Finally, it is to beunderstood that the compositions herein comprise compounds of theinvention in their un-ionized, as well as zwitterionic form, andcombinations with stoiochimetric amounts of water as in hydrates.

[0183] Also included within the scope of this invention are the salts ofthe parental compounds with one or more amino acids. Any of the aminoacids described above are suitable, especially the naturally-occuringamino acids found as protein components, although the amino acidtypically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

[0184] Additional Uses for the Compounds of This Invention The compoundsof the invention are polyfunctional. As such they represent a uniqueclass of monomers for the synthesis of polymers. By way of example andnot limitation, the polymers prepared from the compounds of thisinvention include polyamides, polyesters and mixed polyester-polyamides.

[0185] The present compounds are used as monomers to provide access topolymers having unique pendent functionalities. The compounds of thisinvention are useful as comonomers with monomers which do not fallwithin the scope of the invention. Polymers of the compounds of thisinvention will have utility as cation exchange agents (polyesters orpolyamides) in the preparation of molecular sieves (polyamides),textiles, fibers, films, formed articles and the like. Polymers areprepared by any conventional method, for example, by cross-linking an—OH or —NH₂ group of the compounds of the invention with a diacidcomonomer. The preparation of these polymers from the compounds of theinvention is conventional per se.

[0186] The compounds of the invention are also useful as a unique classof polyfunctional surfactants. Particularly when R⁴ or R² do not containhydrophilic substituents and are, for example, alkyl, the compounds havethe properties of bi-functional surfactants. As such they have usefulsurfactant, surface coating, emulsion modifying, rheology modifying andsurface wetting properties.

[0187] As polyfunctional compounds with defined geometry and carryingsimultaneously polar and non-polar moieties, the compounds of theinvention are useful as a unique class of phase transfer agents. By wayof example and not limitation, the compounds of the invention are usefulin phase transfer catalysis and liquid/liquid ion extraction (LIX).

[0188] The compounds of the invention optionally contain asymmetriccarbon atoms. As such, they are a unique class of chiral auxiliaries foruse in the synthesis or resolution of other optically active materials.For example, a racemic mixture of carboxylic acids can be resolved intoits component enantiomers by: 1) forming a mixture of diastereomericesters or amides with a compound of the invention containing an —OH or—NH₂ group; 2) separating the diastereomers; and 3) hydrolyzing theester structure. Further, such a method can be used to resolve thecompounds of the invention themselves if optically active acids are usedinstead of racemic starting materials.

[0189] The compounds of this invention are useful as linkers or spacersin preparing affinity absorption matrices, immobilized enzymes forprocess control, or immunoassay reagents. The compounds herein contain amultiplicity of functional groups that are suitable as sites forcross-linking desired substances. For example, it is conventional tolink affinity reagents such as hormones, peptides, antibodies, drugs,and the like to insoluble substrates. These insolublized reagents areemployed in known fashion to absorb binding partners for the affinityreagents from manufactured preparations, diagnostic samples and otherimpure mixtures. Similarly, immobilized enzymes are used to performcatalytic conversions with facile recovery of enzyme. Bifunctionalcompounds are commonly used to link analytes to detectable groups inpreparing diagnostic reagents.

[0190] Many functional groups in the compounds of this invention aresuitable for use in cross-linking. For example, —H and —NH₂ groups.Suitable protection of reactive groups will be used where necessarywhile assembling the cross-linked reagent to prevent polymerization ofthe bifunctional compound of this invention: In general, the compoundshere are used by linking them through hydroxyl or amino groups tocarboxylic or phosphonic acid groups of the first linked partner, thencovalently bonding to the other binding partner through another OH or—NH₂ group. For example a first binding partner such as a steroidhormone is reacted to form an amide bond with the —NH₂ group of acompound of this invention and then this conjugate is cross-linkedthrough a hydroxyl to cyanogen bromide activated Sepaharose, wherebyimmobilized steroid is obtained. Other chemistries for conjugation arewell known. See for example Maggio, “Enzyme-Immunoassay” (CRC, 1988, pp71-135) and references cited therein.

[0191] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow to make the compounds and compositions of the invention and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to insure accuracy with respect tonumbers used (e.g., amounts, temperatures, etc.), but some experimentalerrors and deviations should be taken into account. Unless indicatedotherwise, parts are parts by weight, temperature is in degreesCentigrade, and pressure is at or near atmospheric.

EXAMPLES Example 1

[0192] Lactone 100: A solution of quinic acid (20 kg, 104 mol;[α]_(D)-43.7° (c=1.12, water); “Merck Index 11th ed”., 8071: [α]_(D)−42° to −44° (water)), 2,2-dimethoxypropane (38.0 kg, 365 mol) andp-toluenesulfonic acid monohydrate (0.200 kg, 1.05 mol) in acetone (80kg) was heated at reflux for two hours. The reaction was quenched byaddition of 21% sodium ethoxide in ethanol (0.340 kg, 1.05 mol) and mostof the solvent was distilled in vacuo. The residue was partitionedbetween ethyl acetate (108 kg) and water (30 kg). The aqueous layer wasback-extracted with ethyl acetate (13 kg) and the combined organiclayers were washed with 5% aqueous sodium bicarbonate (14 kg). Most ofthe ethyl acetate was distilled in vacuo to leave a pale yellow solidresidue of 100 which was used directly in the next step.

Example 2

[0193] Hydroxy ester 101: A solution of the crude lactone 100 (from 104mol (−)-quinic acid) in absolute ethanol (70 kg) was treated with 20%sodium ethoxide in ethanol (0.340kg, 1.05 mol). After two hours at roomtemperature, acetic acid (0.072 kg, 1.2 mol) was added and the solventwas distilled in vacuo. Ethyl acetate (36 kg) was added and thedistillation continued to near dryness. The tan solid residue composedof a ca. 5:1 mixture of 101:100 was dissolved in ethyl acetate (9 kg) atreflux and hexane (9 kg) was added. Upon cooling, a white crystallinesolid formed which was isolated by filtration to afford a ca. 6.5:1mixture of 101:100 (19.0 kg, 70% yield).

Example 3

[0194] Mesyl ester 102: A solution of a ca. 6.5:1 mixture (18.7 kg, ca.72 mol) of hydroxy ester 101 and lactone 100 in dichloromethane (77 kg)was cooled to 0-10° C. and treated with methanesulfonyl chloride (8.23kg, 71.8 mol), followed by slow addition of triethylamine (10.1 kg, 100mol). An additional portion of methanesulfonyl chloride (0.84 kg, 7.3mol) was added. After one hour, water (10 kg) and 3% hydrochloric acid(11 kg) were added. The layers were separated and the organic layer waswashed with water (9 kg), then distilled in vacuo to leave a semi-solidresidue composed of a ca. 6.5:1 mixture of mesyl ester 102 and mesyllactone 103. The residue was dissolved in ethyl acetate (11 kg) andcooled to −10° to −20° C. for two hours. Mesyl lactone 103 crystallizedand was separated by filtration and washed with cold ethyl acetate (11kg). The filtrate was concentrated to afford mesyl ester 102 as anorange resin (20.5 kg, 84.3% yield).

Example 4

[0195] Mesyl acetonide 104: A solution of mesyl ester 102 (10.3 kg, 30.4mol) and pyridine (10.4 kg, 183 mol) in dichloromethane (63 kg) wascooled to −20° to −30° C. and treated portionwise with sulfuryl chloride(6.22 kg, 46 mol). After the exothermic reaction subsided, the resultingslurry was quenched with ethanol (2.4 kg), warmed to 0° C., and washedsuccessively with 16% sulfuric acid (35 kg), water (15 kg) and 5%aqueous sodium bicarbonate (1 kg). The organic layer containing a ca.4:1:1 mixture of 104:105:106 was concentrated in vacuo and ethyl acetate(14 kg) was added. The allylic mesylate 105 was selectively removed bytreatment of the ethyl acetate solution with pyrrolidine (2.27 kg, 31.9mol) and tetrakis(triphenylphosphine)palladium(O) (0.0704 kg, 0.061mol)at ambient temperature for five hours, followed by washing with 16%sulfuric acid (48 kg). The organic layer was filtered through a pad ofsilica gel (11 kg) and eluted with ethyl acetate (42 kg). The filtratewas concentrated in vacuo to leave a thick orange oil composed of a ca.4:1 mixture of 104:106. The residue was dissolved in ethyl acetate (5.3kg) at reflux and hexane (5.3 kg) was added. Upon cooling, mesylacetonide 104 crystallized and was separated by filtration and washedwith 14% ethyl acetate in hexane (2.1 kg). After drying in vacuo, 104was obtained as pale yellow needles (4.28 kg, 43.4% yield), mp 102-3° C.

Example 5

[0196] Pentyl ketal 107: A solution of acetonide 104 (8.9 kg, 27.8 mol),3-pentanone (24 kg, 279 mol) and 70% perchloric acid (0.056 kg, 0.39mol) was stirred for 18 hours. The volatiles were distilled in vacuo atambient temperature and fresh 3-pentanone (30 kg, 348 mol) was addedgradually as the distillation progressed. The reaction mixture wasfiltered, toluene (18 kg) was added, and the resulting solution waswashed successively with 6% aqueous sodium bicarbonate (19 kg), water(18 kg) and brine (24 kg). The organic layer was concentrated in vacuoand toluene (28 kg) was added gradually as the distillation progressed.When no more distilled, the residual orange oil was composed of pentylketal 107 (9.7 kg, 100% yield) and toluene (ca. 2 kg).

Example 6

[0197] Pentyl ether 108: A solution of ketal 107 (8.6 kg, 25 mol) indichloromethane (90 kg) was cooled to −30° to −20° C. and treated withborane-methyl sulfide complex (2.1 kg, 27.5 mol) and trimethylsilyltrifluoromethanesulfonate (7.2 kg, 32.5 mol). After one hour, 10%aqueous sodium bicarbonate solution (40 kg) was slowly added. Themixture was warmed to ambient temperature and stirred for 12 hours. Theorganic layer was filtered and concentrated in vacuo to leave a ca. 8:1mixture of 108:109 as a gray waxy solid (7.8 kg, 90% yield).

Example 7

[0198] Epoxide 110: A ca. 8:1 mixture of isomeric pentyl ethers 108:109(7.8 kg, 22.3 mol) in ethanol (26 kg) was treated with a solution ofpotassium hydrogen carbonate (3.52 kg, 35 mol) in water (22 kg). Afterheating at 55°-65° C. for two hours, the solution was cooled and twiceextracted with hexanes (31 kg, then 22 kg). Unreacted 109 remained inthe aqueous ethanol layer. The combined hexane extracts were filteredand concentrated in vacuo to leave epoxide 110 as a flocculent whitecrystalline solid (3.8 kg, 60% yield), mp=54.6° C.

Example 8

[0199] Hydroxy azide 111: A mixture of epoxide 110 (548 g, 2.0 mol),sodium azide (156 g, 2.4 mol) and ammonium chloride (128.4 g, 2.4 mol)in water (0.265 L) and ethanol (1.065 L) was heated at 70°-75° C. foreight hours. Aqueous sodium bicarbonate (0.42 L of 8% solution) wasadded and the ethanol was distilled in vacuo. The aqueous residue wasextracted with ethyl acetate (1 L) and the extract was washed with water(0.5 L). The water wash was back-extracted with ethyl acetate (0.5 L).The combined organic extracts were washed with brine (0.5 L), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to leave aca. 10:1 mixture of isomeric hydroxy azides 111:112 (608 g, 102% yield)as a dark brown oil.

Example 9

[0200] Aziridine 113: A ca. 10:1 mixture of hydroxy azides 111:112 (608g, 2.0 mol) was three times co-evaporated in vacuo from anhydrousacetonitrile (3×0.3 L) and then dissolved in anhydrous acetonitrile (1L). A solution of anhydrous triphenylphosphine (483 g, 1.84 mol) inanhydrous tetrahydrofuran (0.1 L) and anhydrous acetonitrile (0.92 L)was added dropwise over two hours. The mixture was heated at reflux forsix hours then concentrated in vacuo to leave a golden paste composed ofaziridine 113, triphenylphosphine oxide and traces oftriphenylphosphine. The paste was triturated with diethyl ether (0.35L). Most of the insoluble triphenylphosphine oxide was removed byfiltration and washed with diethyl ether (1.5 L). The filtrate wasconcentrated in vacuo to leave a dark brown oil which was dissolved in20% aqueous methanol and extracted three times with hexanes (3×1 L) toremove triphenylphosphine. The hexane extracts were back-extracted with20% aqueous methanol (0.5 L) and the combined aqueous methanol layerswere concentrated in vacuo. The residue was twice co-evaporated in vacuofrom anhydrous acetonitrile (2×0.5 L) to leave a dark brown oil composedof aziridene 113 (490 g, 96.8% yield) and triphenylphosphine oxide (ca.108 g) which was used directly in the next step.

Example 10

[0201] Acetamido azide 115: A mixture of aziridine 113 (490 g, 1.93 mol)and triphenylphosphine oxide (ca. 108 g), sodium azide (151 g, 2.33 mol)and ammonium chloride (125 g, 2.33 mol) in dimethylformamide (1.3 L) washeated at 80°-85° C. for five hours. Sodium bicarbonate (32.8 g, 0.39mol) and water (0.66 L) were added. The amino azide 114 was isolatedfrom the reaction mixture by six extractions with hexanes (6×1 L). Thecombined hexane extracts were concentrated in vacuo to ca. 4.5 L totalvolume and dichloromethane (1.04 L) was added. Aqueous sodiumbicarbonate (4.2 L of 8% solution, 3.88 mol) was added, followed byacetic anhydride (198 g, 1.94 mol). After stirring for one hour atambient temperature, the aqueous layer was discarded. The organic phaseswere concentrated in vacuo to 1.74 kg total weight and dissolved withethyl acetate (0.209 L) at reflux. Upon cooling, acetamido azide 115crystallized and was isolated by filtration. After washing with cold 15%ethyl acetate in hexane (1 L) and drying in vacuo at ambienttemperature, pure 115 was obtained as off-white crystals (361 g, 55%yield), mp 126-132° C.

Example 11

[0202] Acetamido amine 116: A mixture of azide 115 (549 g, 1.62 mol) andLindlar catalyst (50 g) in abs. ethanol (3.25 L) was stirred foreighteen hours while hydrogen (1 atm.) was bubbled through the mixture.Filtration through Celite and concentration of the filtratein vacuoafforded 116 as a foam which solidified on standing (496 g, 98% yield).

Example 12

[0203] Phosphate salt of 116: A solution of acetamido amine 116 (5.02 g,16.1 mmol) in acetone (75 mL) at reflux was treated with 85% phosphoricacid (1.85 g, 16.1 mmol) in abs. ethanol (25 mL). Crystallizationcommenced immediately and after cooling to 0° C. for 12 hours theprecipitate was collected by filtration to afford 116*H₃PO₄ as longcolorless needles (4.94 g, 75% yield; [α]_(D) −39.9° (c=l, water)), mp2034° C.

Example 13

[0204] Hydrochloride salt of 116: A solution of acetamido amine 116 (2.8g, 8.96 mmol) in abs. ethanol (9 mL) was treated with 2.08 M hydrogenchloride in ethanol (8.6 mL, 17.9 mmol). Most of the ethanol wasevaporated in vacuo and the oily residue was stirred with ethyl acetate(20 mL) until solid formed. Hexanes (20 mL) were gradually added to thestirred mixture. After one hour at ambient temperature, the solid wascollected by filtration, washed with diethyl ether and dried in vacuo.This afforded 116.HCl as an off-white solid (2.54 g, 81% yield; [α]_(D)−43° (c=0.4, water)), mp206° C.

[0205] All literature and patent citations above are hereby expresslyincorporated by reference in their entirety at the locations of theircitation. Specifically cited sections or pages of the above cited worksare incorporated by reference with specificity.

[0206] Whenever a compound described herein is substituted with morethan one of the same designated group, such as, by was of example andnot limitation, “R⁷”, “R⁸”, “R⁹”, “R²⁰”, or “R²²”, then it will beunderstood that each of the groups may be the same or different, i.e.,each group is independently selected. So for example, the phrase “R²²is” is synonymous with the phrase “each R²² is independently”.

[0207] The invention has been described in detail sufficient to allowone of ordinary skill in the art to make and use the subject matter ofthe following claims. It is apparent that certain modifications of themethods and compositions of the following claims can be made within thescope and spirit of the invention.

What is claimed is:
 1. A process for preparation of compounds of theformula:

wherein: R¹ is a cyclic hydroxy protecting group; R² is a carboxylicacid protecting group; R³ is a hydroxy protecting group; and each R²⁰ isindependently H or an alkyl of 1 to 12 carbon atoms; which processcomprises reaction of a compound of the formula:

with a dehydrating reagent.
 2. The process of claim 1 which furthercomprises separating compound 5 by treatment with a noble metal complex.3. The process of claim 1 wherein compound 4 is of the formula:


4. A process for preparation of compounds of the formula:

wherein: R² is a carboxylic acid protecting group; R³ is a hydroxyprotecting group; R⁴ is —C(R³⁰)₃; R⁵ is H or R³; R⁷ is H or an aminoprotecting group; R8 is H or R²; R⁹ is H or a thiol protecting group;each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms; eachR²¹ is independently R², Br, Cl, F, I CN, NO₂ or N₃; each R²² isindependently F, Cl, Br, I, CN, N₃, —NO₂, —OR⁵, —OR20, —N(R²⁰)₂,—N(R²⁰)(R⁷), —N(R⁷)₂, —SR²⁰, —SR⁹, —S(O)R²t, —S(O)₂R²⁰, —S(O)OR²⁰),—S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, C(O)OR₂₀, —C(O)OR⁸, OC(O)R²⁰,—N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰, —N(R²⁰)(C(O)OR²⁰), —N(R⁷)(C(O)OR²⁰,—C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂, —C(NR²⁰)(N(R²⁰)₂),—C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰))(N(R²⁰)(R⁷)), —C(N(R₇))(N(R²⁰)(R⁷)),—C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂), —N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂), —N(R⁷)C (N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)₂), —N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R²⁰))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)), —N(R⁷)C(N(R²⁰))(N(R⁷)₂),—N(R²⁰)C(N(R⁷))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷)or W; R²³ is independently alkyl of 1 to 11 carbon atoms, alkenyl of 2to 11 carbon atoms, or alkynyl of 2 to 11 carbon atoms; R²⁴ isindependently R²³ wherein each R²³ is substituted with 0 to 3 R²²groups; R²⁴a is independently alkylene of 1 to 11 carbon atoms,alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon atomsany one of which alkylene, alkenylene or alkynylene is substituted with0-3 R²² groups; R²⁸ is independently alkyl of 1 to 12 carbon atoms,alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹is independently R²² or R²⁸ wherein each R²⁸ is substituted with 0 to3R²² groups; each R³⁰ is independently H, R²⁴, W or —R^(24a)W; and W iscarbocycle or heterocycle wherein any one of which carbocycle orheterocycle is substituted with 0 to 3 R²⁹ groups; which processcomprises reaction of a compound of the formula:

wherein R³¹ is a ketal or acetal, with a lewis acid reagent; providedthat R⁴, taken as a whole, contains: 0 to 3 W groups substituted with 0to 3 R²⁹ groups; and, in addition, 1 to 12 carbon atoms substituted with0 to 3 R²² groups.
 5. The process of claim 4 which further comprisestreating compound 10 with a reducing reagent.
 6. The process of claim 4wherein compound 11 is of the formula;


7. A process for preparation of compounds of the formula:

wherein: R² is a carboxylic acid protecting group; R³ is a hydroxyprotecting group; R⁴ is —C(R³⁰)₃; R⁵ is H or R³; R⁷ is H or an aminoprotecting group; R⁸ is H or R²; R⁹ is H or a thiol protecting group;each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms; eachR²¹ is independently R²⁰, Br, Cl, F, I CN, NO₂ or N₃; each R²² isindependently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵, —OR²⁰, —N(R²⁰)₂,—N(R²⁰)(R⁷), —N(R⁷)₂, -SR²⁰, -SR⁹, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)OR²⁰,—S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, C(o)OR²O, —C(O)OR⁸, —OC(O)R²⁰,—N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰), —N(R⁷)(C(O)OR²⁰),—C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂, —C(NR²⁰)(N(R²⁰)₂),—C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰)) (N(R²⁰)(R⁷)), —C(N(R⁷))(N(R²⁰)(R⁷)),—C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂), —N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),—N(R²⁰)C(N(R²⁰) )(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷) or W; R²³ isindependently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbonatoms, or alkynyl of 2 to 11 carbon atoms; R²⁴ is independently R²³wherein each R²³ is substituted with 0 to 3 R²² groups; R²⁴a isindependently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11carbon atoms, or alkynylene of 2-11 carbon atoms any one of whichalkylene, alkenylene or alkynylene is substituted with 0-3 R²² groups;R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹ is independentlyR²² or R²⁸ wherein each R²⁸ is substituted with 0 to 3 R²² groups; eachR³⁰ is independently H, R²⁴, W or —R^(24a)W; W is carbocycle orheterocycle wherein any one of which carbocycle or heterocycle issubstituted with 0 to 3 R²⁹ groups; which process comprises reaction ofa compound of the formula:

with a reducing reagent; provided that R⁴, taken as a whole, contains: 0to 3 W groups substituted with 0 to 3 R²⁹ groups; and, in addition, 1 to12 carbon atoms substituted with 0 to 3 R²² groups.
 8. The process ofclaim 7 wherein the reducing reagent is a trisubstituted phosphinereducing reagent.
 9. The process of claim 7 wherein compound 31 is ofthe formula:


10. A process for preparation of compounds of the formula:

wherein: R² is a carboxylic acid protecting group; R³ is a hydroxyprotecting group; R⁴ is —C(R³⁰)₃; R⁵ is H or R³; R⁷ is H or an aminoprotecting group; R⁸ is H or R²; R⁹ is H or a thiol protecting group;each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms; eachR²¹ is independently R²⁰, Br, Cl, F, I CN, NO₂ or N₃; each R²² isindependently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵, —OR²⁰, —N(R²⁰)₂,—N(R²⁰)(R⁷), —N(R⁷)₂, —SR²⁰, —SR⁹, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)OR²⁰,—S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, —C(O)OR²⁰, —C(O)OR⁸, —OC(O)R²⁰,—N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰), —N(R⁷)(C(O)OR²⁰),—C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂, —C(NR²⁰)(N(R²⁰)₂),—C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰))(N(R²⁰)(R⁷)), —C(N(R⁷))(N(R²⁰)(R⁷)), —C(N(R²⁰) )(N(R⁷)₂), —C (N(R⁷))(N(R⁷)₂), —N(R²⁰)C(N(R²⁰) )(N(R²⁰)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷) or W; R²³ isindependently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbonatoms, or alkynyl of 2 to 11 carbon atoms; R²⁴ is independently R²³wherein each R²³ is substituted with 0 to 3 R²² groups; R^(24a) isindependently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11carbon atoms, or alkynylene of 2-11 carbon atoms any one of whichalkylene, alkenylene or alkynylene is substituted with 0-3 R²² groups;R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹ is independentlyR²² or R²⁸ wherein each R²⁸ is substituted with 0 to 3 R²² groups; eachR³⁰ is independently H, R²⁴, W or —R^(24a)W; W is carbocycle orheterocycle wherein any one of which carbocycle or heterocycle issubstituted with 0 to 3 R²⁹ groups; and Y¹ is a mono-, di- orunsubstituted amino group; which process comprises reaction of acompound of the formula:

with an amine reagent; provided that R⁴, taken as a whole, contains: 0to 3 W groups substituted with 0 to 3 R²⁹ groups; and, in addition, 1 to12 carbon atoms substituted with 0 to 3 R²² groups.
 11. The process ofclaim 10 wherein the amine reagent is a phthalimide reagent.
 12. Theprocess of claim 10 wherein compound 41 is of the formula:


13. A process for preparation of compounds of the formula:

wherein: R² is a carboxylic acid protecting group; R³ is a hydroxyprotecting group; R⁴ is —C(R³⁰)₃; R⁵is H or R³; R⁷ is H or an aminoprotecting group; R⁸ is H or R²; R⁹ is H or a thiol protecting group;each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms; eachR²¹ is independently R²⁰, Br, Cl, F, I CN, NO₂ or N₃; each R²² isindependently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵, —OR²⁰, —N(R²⁰)₂,—N(R²⁰)(R⁷), —N(R⁷)₂, —SR²⁰, —SR⁹, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)OR²⁰,—S(O)OR⁸, —S(O)₂₀R²⁰, —S(O)₂OR⁸, —C(O)OR²⁰, —C(O)OR⁸, —OC(O)R²⁰,—N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰), —N(R⁷)(C(O)OR²⁰),—C(O)N(R²⁰)₂, —C(O)N(R⁷) (R²⁰), —C(O)N(R⁷)₂, —C(NR²⁰)(N(R²⁰)₂),—C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰))(N(R²⁰)(R⁷)), —C(N(R⁷))(N(R²⁰)(R⁷)),—C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂), —N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰) (R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷) or W; R²³ isindependently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbonatoms, or alkynyl of 2 to 11 carbon atoms; R²⁴ is independently R²³wherein each R²³ is substituted with 0 to 3 R²² groups; R^(24a) isindependently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11carbon atoms, or alkynylene of 2-11 carbon atoms any one of whichalkylene, alkenylene or alkynylene is substituted with 0-3 R²² groups;R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹ is independentlyR²² or R²⁸ wherein each R²⁸ is substituted with 0 to 3 R²² groups; eachR³⁰ is independently H, R²⁴, W or —R^(24a)W; W is carbocycle orheterocycle wherein any one of which carbocycle or heterocycle issubstituted with 0 to 3 R²⁹ groups; and Y¹ is a mono-, di- orunsubstituted amino group; which process comprises reaction of acompound of the formula:

with an oxidizing reagent; provided that R⁴, taken as a whole, contains:0 to 3 W groups substituted with 0 to 3 R²⁹ groups; and, in addition, 1to 12 carbon atoms substituted with 0 to 3 R²² groups.
 14. The processof claim 13 wherein compound 51 is of the formula:


15. A process for preparation of a compound of the formula:

wherein: R² is a carboxylic acid protecting group; R³ is a hydroxyprotecting group; R⁴ is —C(R³⁰)₃; R⁵ is H or R³; R⁷ is H or an aminoprotecting group; R⁸ is H or R²; R⁹ is H or a thiol protecting group;each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms; eachR²¹ is independently R²⁰ ₁ Br, Cl, F, I CN, N0₂ or N₃; each R²² isindependently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵, CR²⁰, —N(R²⁰)₂,—N(R²⁰)(R⁷), —N(R⁷)₂, —SR²⁰, -SR⁹, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)OR²⁰,—S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, —C(O)OR²⁰, —C(O)OR⁸, —OC(O)R²⁰,—N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰), —N(R⁷)(C(O)OR²⁰),—C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂, —C(NR²⁰)(N(R²⁰)₂), —C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰))(N(R²⁰)(R⁷)), —C(N(R⁷))(N(R²⁰)(R⁷)),—C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂), —N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =0, =S, =N(R²⁰), =N(R⁷) or W; R23 isindependently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbonatoms, or alkynyl of 2 to 11 carbon atoms; R²⁴ is independently R²³wherein each R²³ is substituted with 0 to 3 R²² groups; R^(24a) isindependently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11carbon atoms, or alkynylene of 2-11 carbon atoms any one of whichalkylene, alkenylene or alkynylene is substituted with 0-3 R²² groups;R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹ is independentlyR²² or R²⁸ wherein each R²⁸ is substituted with 0 to 3 R²² groups; eachR³⁰ is independently H, R²⁴, W or —R^(24a)W; W is carbocycle orheterocycle wherein any one of which carbocycle or heterocycle issubstituted with 0 to 3 R²⁹ groups; and Y¹ is a mono-, di- orunsubstituted amino group; which process comprises reaction of acompound of the formula:

with a base; provided that R⁴, taken as a whole, contains: 0 to 3 Wgroups substituted with 0 to 3 R²⁹ groups; and, in addition, 1 to 12carbon atoms substituted with 0 to 3 R²² groups.
 16. The process ofclaim 15 wherein compound 61 is of the formula:


17. A process for preparation of compounds of the formula:

wherein: R² is a carboxylic acid protecting group; R³ is a hydroxyprotecting group; R⁴ is —C(R³⁰)₃; R⁵ is H or R³; R⁷ is H or an aminoprotecting group; R⁸ is H or R²; R⁹ is H or a thiol protecting group;each R²⁰ is independently H or an alkyl of 1 to 12 carbon atoms; eachR²¹ is independently R²⁰, Br, Cl, F, I CN, NO₂ or N₃; each R²² isindependently F, Cl, Br, I, —CN, N₃, —NO₂, —OR⁵, —OR²⁰, —N(R²′)₂,—N(R²⁰)(R⁷), —N(R7)₂, —SR²⁰, —SR⁹, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)OR²⁰,—S(O)OR⁸, —S(O)₂OR²⁰, —S(O)₂OR⁸, —C(O)OR²⁰, —C(O)OR⁸, OC(O)R²⁰,—N(R²⁰)(C(O)R²⁰), —N(R⁷)(C(O)R²⁰), —N(R²⁰)(C(O)OR²⁰), —N(R⁷)(C(O)OR²⁰),—C(O)N(R²⁰)₂, —C(O)N(R⁷)(R²⁰), —C(O)N(R⁷)₂, —C(NR²⁰)(N(R²⁰)₂),—C(N(R⁷))(N(R²⁰)₂), —C(N(R²⁰)) (N(R²⁰)(R⁷)), —C(N(R⁷))(N(R²⁰)(R⁷)),—C(N(R²⁰))(N(R⁷)₂), —C(N(R⁷))(N(R⁷)₂), —N(R²⁰)C(N(R²⁰))(N(R²⁰)₂),—N(R²⁰)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)₂),—N(R⁷)C(N(R²⁰))(N(R²⁰)(R⁷)), —N(R²⁰)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R²⁰)C(N(R²⁰))(N(R⁷)₂), —N(R⁷)C(N(R⁷))(N(R²⁰)(R⁷)),—N(R⁷)C(N(R²⁰))(N(R⁷)₂), —N(R²⁰)C(N(R⁷))(N(R⁷)₂),—N(R⁷)C(N(R⁷))(N(R⁷)₂), =O, =S, =N(R²⁰), =N(R⁷) or W; R²³ isindependently alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbonatoms, or alkynyl of 2 to 11 carbon atoms; R²⁴ is independently R²³wherein each R²³ is substituted with 0 to 3 R²² groups; R^(24a) isindependently alkylene of 1 to 11 carbon atoms, alkenylene of 2 to 11carbon atoms, or alkynylene of 2-11 carbon atoms any one of whichalkylene, alkenylene or alkynylene is substituted with 0-3 R²² groups;R²⁸ is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12carbon atoms, or alkynyl of 2 to 12 carbon atoms; R²⁹ is independentlyR²² or R²⁸ wherein each R²⁸ is substituted with 0 to 3 R²² groups; eachR³⁰ is independently H, R²⁴, W or —R^(24a)W; W is carbocycle orheterocycle wherein any one of which carbocycle or heterocycle issubstituted with 0 to 3 R²⁹ groups; and Y¹ is a mono-, di- orunsubstituted amino group; which process comprises reaction of acompound of the formula:

with a reductive amination reagent; provided that R⁴, taken as a whole,contains: 0 to 3 W groups substituted with 0 to 3 R²⁹ groups; and, inaddition, 1 to 12 carbon atoms substituted with 0 to 3 R²² groups. 18.The process of claim 17 wherein compound 71 is of the formula:


19. A process according to any one or sequential combination ofprocesses AA, AB, AC, AD, AE, AF, AG, AH, AL, AJ, or AK of Schemes 1and2.
 20. A process according to any one or sequential combination ofthe processes of Example 1, Example 2, Example 3, Example ₄, Example 5,Example 6, Example 7, Example 8, Example 9, Example 10, Example 11,Example 12 or Example
 13. 21. A process according to any one orsequential combination of processes AL, AM, AN, AO, or AP of Scheme 3.22. A process for preparation of compounds of the formula:

wherein: R¹ is a cyclic hydroxy protecting group; R² is a carboxylicacid protecting group; R³ is a hydroxy protecting group; and each R²⁰ isindependently H or an alkyl of 1 to 12 carbon atoms; which processcomprises reaction of a compound of the formula:

with a dehydrating reagent; provided that excluded is the process ofconverting a compound of the formula:

to a compound of the formula:

by reaction with POCl₃ in pyridine.
 23. The process of claim 22 whereincompound 4 is of the formula:


24. A process for the preparation of a compound of the formula:

which process comprises reaction of a compound of the formula:

with a dehydrating reagent and a noble metal complex.
 25. A process forthe preparation of a compound of the formula:

which process comprises reaction of a compound of the formula:

with a Lewis acid reagent.
 26. A process for the preparation of acompound of the formula:

wherein R is a mono-, di- or unsubstituted amino group, which processcomprises reaction of a compound of the formula:

with an amine reagent.
 27. A compound of the formula:


28. A compound of the formula:


29. A compound of the formula:


30. A compound of the formula:


31. A compound of the formula:


32. A compound of the formula:


33. A compound of the formula:


34. A compound of the formula:


35. A compound of the formula:


36. A process for preparing the compound of the formula 116

which comprises a) converting the compound of formula 110

to the compound of formula 111:

b) converting the compound of formula 111 to the compound of formula113:

c) converting the compound of formula 113 to the compound of formula114:

d) converting the compound of formula 114 to the compound of formula115:

e) converting the compound of formula 115 to the compound of formula116.
 37. The process of claim 36 wherein a) in step a) compound 110 istreated with sodium azide; b) in step b) compound 111 is treated with areducing reagent, in particular triphenylphosphine; c) in step c)compound 113 is treated with sodium azide; d) in step d) compound 114 istreated with an acetylating reagent; and e) in step e) compound 115 issubjected to catalytic hydrogenation.
 38. A process for preparing thecompound of formula 116:

which comprises a) converting the compound of formula 201

to the compound of formula 202

b) converting the compound of formula 202 to the compound of formula 203

c) converting the compound of formula 203 to the compound of formula 204

d) converting the compound of formula 204 to the compound of formula 205

e) converting the compound of formula 205 to the compound of formula116.
 39. The process of claim 38 wherein a) in step a) compound 201 istreated with an amine reagent; b) in step b) compound 202 is treatedwith an oxidizing reagent; c) in step c) compound 203 is treated with abase: d) in step d) compound 204 is treated with a reductive aminationreagent; and e) in step e) compound 205 is treated with an acetylatingreagent.